scholarly journals Use of a conformational switching aptamer for rapid and specific ex vivo identification of central nervous system lymphoma in a xenograft model

2018 ◽  
Author(s):  
Joseph Georges ◽  
Xiaowei Liu ◽  
Hao Yan ◽  
Trent Anderson ◽  
Burt Feuerstein ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Central Nervous System Lymphoma ◽  
Conformational Switching

scholarly journals Use of a Conformational Switching Aptamer for Rapid and Specific Ex Vivo Identification of Central Nervous System Lymphoma in a Xenograft Model

PLoS ONE ◽  
2015 ◽  
Vol 10 (4) ◽  
pp. e0123607 ◽  
Author(s):  
Joseph F. Georges ◽  
Xiaowei Liu ◽  
Jennifer Eschbacher ◽  
Joshua Nichols ◽  
Michael A. Mooney ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Central Nervous System Lymphoma ◽  
Conformational Switching

scholarly journals Pathologic Correlates of Primary Central Nervous System Lymphoma Defined in an Orthotopic Xenograft Model

2009 ◽  
Vol 15 (6) ◽  
pp. 1989-1997 ◽  
Author(s):  
Cigall Kadoch ◽  
Eduard B. Dinca ◽  
Ramona Voicu ◽  
Lingjing Chen ◽  
Diana Nguyen ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Xenograft Model ◽  
Central Nervous System Lymphoma ◽  
Orthotopic Xenograft ◽  
Orthotopic Xenograft Model

scholarly journals IMMU-50. BBB CROSSING NANO-IMMUNOMEDICINE COMBINATION THERAPY TO TREAT BRAIN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii115-ii115
Author(s):  
Tao Sun ◽  
Jiyuan Yang ◽  
Maximilian Gamburg ◽  
Vladimir Ljubimov ◽  
Zachary Grodzinski ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Flow Cytometry ◽  
Nervous System ◽  
Ex Vivo ◽  
Central Nervous System Lymphoma ◽  
Phase Iii ◽  
Spectral Flow ◽  
Rna Seq ◽  
M1 Macrophage ◽  
Synthesis Strategy

Abstract INTRODUCTION Lack of standard treatment of Primary Central Nervous System Lymphoma (PCNSL) was acknowledged in phase III intergroup study (HOVON 105/ALLG NHL 24). PCNSL incidence is increasing for unknown reasons, particularly among persons over 65 years. One of the major limitations of successful treatment of PCNSL is the blood-brain barrier (BBB), which prevents drug delivery into the brain. METHODS Polymer nanoconjugate based on biodegradable poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA) was used for treatment of BALB/C mice with intracranially inoculated murine A20 lymphoma. PHPMA-based nanoconjugates have defined synthesis strategy for BBB transcytosis, tumor targeting, and cancer cell killing. Nano immunodrug PHPMA/AP-2/Fab’/c-Myc inhibitor/H6 conjugate contains multiple AP-2 peptides for efficient delivery across the BBB and Fab’ fragments of αCD20 mouse Ab for CD20 receptor crosslinking on PCNSL cells. c-Myc inhibitor bound via a disulfide bond is transferred to the cytoplasm followed by cleavage. The therapeutic efficacy and survival were evaluated together with spectral flow cytometry and RNA-seq bioinformatic analysis of tumor tissues. RESULTS Nanoconjugates were able to penetrate BBB and accumulate in brain parenchyma. The best survival results were obtained for the group where nanoconjugate with αCD20 Fab’ causing tumor cell apoptosis and c-Myc antisense inhibitor was combined with αPD-1 checkpoint inhibitor. Survival compared to PBS-treated controls was significant (P=0.0006 by ANOVA). Ex vivo analysis of A20 brain lymphoma tissue after treatment with nanoconjugates demonstrated reduction of Tregs, associated with downregulation of IL-10 and IL-1β in plasma. Spectral flow cytometry revealed activation of tumor infiltrating T lymphocytes and M1 macrophages in lead nanodrug treated groups. RNA-seq data correlated with flow cytometry results indicating the activation of genes linked to IFN-γ pathway important for anti-tumor response and M1 macrophage activation. Immunostaining confirmed a marked increase of M1-specific iNOS expression in the nanodrug-treated tumors. Support: NIH grants: R01 CA188743, R01 CA206220, R01 CA209921

scholarly journals CBMS-04 Novel xenograft model to clarify tumor progressive mechanism and therapeutic target in primary central nervous system lymphoma

2020 ◽  
Vol 2 (Supplement_3) ◽  
pp. ii4-ii4
Author(s):  
Kensuke Tateishi ◽  
Yohei Miyake ◽  
Masahito Kawazu ◽  
Taishi Nakamura ◽  
Nobuyoshi Sasaki ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Xenograft Model ◽  
Central Nervous System Lymphoma ◽  
Genetic Alterations ◽  
Pathogenic Mechanisms ◽  
Dismal Prognosis ◽  
Orthotopic Xenografts

Abstract Primary central nervous system lymphoma (PCNSL) is a rare lymphoma of the central nervous system and has a dismal prognosis despite intensive chemotherapy. Recent genomic analyses have identified recurrent genetic alterations in Primary central nervous system lymphoma (PCNSL). However, lack of clinically representative PCNSL models has diminished our understanding of the pathogenic mechanisms of those genetic events. Here, we established 14 patient-derived orthotopic xenografts (PDOXs). Comprehensive analysis showed that PDOXs faithfully retained the phenotypic, metabolic, and genetic features with 100 % concordance of MYD88 and CD79B mutations present in immuno-competent PCNSL patients. Notably, orthotopic xenograft formation was consistently dependent on deregulated signaling through the RelA/p65-hexokinase 2 (HK-2) axis. MYD88/CD79B mutations and Pin1 activation, or LMP1 and Pin1 activation, converge on the RelA/p65-HK-2 signaling in immunocompetent and EBV-positive PCNSL, respectively. Genetic and pharmacological inhibition of this key signaling axis potently suppressed PCNSL tumor growth in vitro and in vivo. Additionally, our models further offer a platform for predicting clinical chemotherapeutics efficacy. Therefore, our models provide critical insights into pathogenic mechanisms and therapeutic discovery in PCNSL.

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